Influenza virus belongs to the family Orthomyxoviridae and the viral genome is formed by eight segments of negative-sense, single-stranded RNAs. Influenza virus is a major health concern and significant economic burden throughout the world (23). In the United States, influenza infections are responsible for over 200,000 hospitalizations, and an average of 36,000 deaths every year (33). Fear of a devastating influenza pandemic, similar to the Spanish influenza pandemic in 1918/1919 which killed 40-50 million people worldwide, has also been increased in recent years (24). On Jun. 11, 2009, the World Health Organization (WHO) declared the spread of the 2009 influenza A (H1N1) virus (initially known as Swine Flu) as a global influenza pandemic (8). Outbreaks of avian H5N1 influenza increased awareness and elevated vigilance against the occurrence of an influenza pandemic (3). Many strains of circulating seasonal influenza viruses, and strains of the avian H5N1 influenza virus with pandemic potential, were found to be resistant to anti-viral drugs, amplifying health care concerns (6). Identifying new therapeutic targets and understanding the mechanisms of host-virus interactions are important biomedical goals.
Sphingolipids are bioactive lipid mediators characterized by the presence of a serine head group with one or two fatty acid tails (4). Sphingosine, and its downstream product sphingosine 1-phosphate (S1P), have emerged as the modulators of multiple cellular processes, such as cell growth, survival, differentiation, and cell migration, and are being investigated as potential leads for the development of therapeutic agents. One example is the sphingosine analog FTY720, which was recently approved for the treatment of multiple sclerosis by the FDA as an orally-administrable drug (12). S1P that is generated inside cells can trigger intracellular signaling pathways, and S1P that is secreted can act as an exogenous lipid mediator, stimulating S1P receptor-mediated signaling pathways (29).
The level of S1P is tightly regulated by a variety of S1P-metabolizing enzymes, including sphingosine kinases (SK) and S1P lyases (SPL). Synthesis of S1P from sphingosine is catalyzed by SK, while SPL catalyzes the degradation of S1P to phosphoethanolamine and hexadecanal (30). These S1P-metabolizing enzymes were revealed to modulate diverse cellular stresses induced by anti-cancer drugs (20), DNA damage (26), or serum deprivation (25). Cells overexpressing sphingosine kinase 1 (SK1) displayed increased resistance to a variety of anti-cancer drugs, such as cisplatin, carboplatin, and doxorubicin (20), and cells overexpressing SPL were shown to be more sensitive to drug-mediated cell death (21).
A phosphorylated sphingosine analog, AAL-R, was recently shown to display immunomodulatory activity to alleviate influenza virus-induced immune pathology (17, 18). This analog acted directly on S1P receptors to regulate the expression of inflammatory cytokines, although it did not significantly alter the propagation of influenza virus (18). The role of intracellular S1P-metabolizing enzymes in host cellular defense mechanisms that target viral infections has not been previously studied in any great detail.
In view of these observations, there is a need to provide new and improved methods for the prevention or treatment of viral infections, by targeting cellular processes required for viral replication that can be inhibited or delayed by modulating the level or activity of polypeptides involved in metabolism of S1P and similar lipid mediators.